The long-term objective of our research is to elucidate the mechanisms of precise neuronal targeting during development of the central nervous system (CNS): Specifically, we hope to gain an understanding of the molecular mechanisms underlying the phenomenon of topographic mapping in the visual system. In the pursuit of this goal, we will learn a great deal about neuronal development, which will prove useful in the understanding of both developmental and degenerative neuronal disorders. We will investigate the role of the cell surface ligands ephrin-As and their receptors, EphAs, in the precise topographic mapping of the visual system. We hypothesize that regulation of EphA/ephrin-A interactions are important for proper neuronal targeting. To test this we have developed two specific aims. In Aim 1, we will develop conditional knockout mouse models to delete ephrin-As specifically from the retina, midbrain, or cortex of developing mice. By specifically deleting ephrin-As, we will distinguish between three proposed models for the role of ephrins in neuronal targeting. In Specific Aim 2, we will determine the role of ephrin-As in the integration of sensory information in the brain. Detection, processing, and integration of multiple sensory inputs are necessary for survival. We will test the hypothesis that ephrin-As play an important role in ensuring that visual and somatosensory information are in register in the mouse superior colliculus using axon tracing methods in ephrin-A knockout models. Understanding the role of ephrins in this process will lead to insights into the integration of sensory information in 'higher'cortical areas responsible for attention, planning, and personality. In this study, we propose to use genetic mouse models to achieve a better understanding of the precise development of the visual system and CMS. Understanding this process will have broad impact in the treatment of developmental neurological disorders, such as generalized seizures, attention deficit hyperactivity disorder, and autism, as well as degenerative disorders, such as macular degeneration, Alzheimer's disease, and Parkinson's disease.